1. Field of the Invention
The present invention relates to a novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, a preparation method thereof, and a pharmaceutical composition for the prevention and treatment of metabolic disease comprising the same as an active ingredient.
2. Description of the Related Art
Diabetes is a serious disease that continually threatens our health and at least a hundred million people have been suffering over the world. Diabetes can be classified into two clinical symptom categories, which are type I diabetes and type II diabetes. Type I diabetes, informed as insulin-dependent diabetes mellitus (IDDM), is caused by autoimmune destruction of pancreatic beta cells that produce insulin, so that it requires regular administration of exogenous insulin. Type II diabetes, informed as non insulin-dependent diabetes mellitus (NIDDM), is resulted from the defect in regulating blood sugar. So, those people who have type II diabetes characteristically show defect in insulin secretion or insulin resistance, suggesting that they hardly have insulin secreted in vivo or cannot utilize insulin efficiently.
Diabetes is characterized by high concentration of glucose in blood and urine, by which this disease causes polyuria, thirst, hunger, and other lipid and protein metabolism related problems. Diabetes can cause life threatening complications such as vision loss, renal failure, and heart disease. Diabetes is also a reason of retinal damage, and increases the risk of cataract and glaucoma. Diabetes also lowers response to the pain relating to nerve injury in legs and feet and can be a reason of significant infection.
Recent drugs to treat diabetes are insulin, insulin-secretagogue, glucose lowering effector, peroxisome proliferator-activated receptor activator, etc. However, recent treatment methods have problems of inducing low blood sugar, increasing body weight, losing reactivity to the treatment drug over the time, causing gastro-intestinal tract problems and edema, etc. Therefore, studies have been undergoing to introduce a more effective and efficient treatment method. One of those attempts is to use G-protein coupled receptor (GPCR).
GPR40 has recently been identified as one of G-protein coupled receptor (GPCR). It is known as free fatty acid receptor I, which is over-expressed in β-cells in pancreas. Intracellular calcium concentration is increased by such compound that activates GPR40 (FFAR1) and accordingly glucose-stimulated insulin secretion (GSIS) is promoted (Current Drug Targets, 2008, 9, 899-910). When the GPR40 activator was introduced in a normal mouse or a transgenic mouse being apt to have diabetes and glucose tolerance test followed, it showed increased glucose tolerance. The treated mouse demonstrated a short-term increase of insulin in blood plasma. It was confirmed from the study on the functions of GPR40 that free fatty acid which is the ligand of GPR40 was acting in pancreatic β cells, and as a result the β cells secreted insulin glucose concentration dependently. From the analysis with GPR knockout mouse, it was confirmed that GPR40 was involved in obesity and diabetes (Can J Diabetes 2012, 36, 275-280). Therefore, GPR40 is regarded as a novel target of diabetes study.
In the course of study on GPR40 activator, the present inventors confirmed that a novel 3-(4-(benzyloxy)phenyl)hex-4-inoic acid derivative, a pharmaceutically acceptable salt thereof, or an optical isomer of the same had GPR40 related activity, resulting in the confirmation of excellent in vivo effect such as the increase of intracellular calcium concentration and the effect of lowering blood glucose, leading to the completion of this invention.